Lipoidal preparations have been extensively studied in an effort to improve drug absorption from the gastrointestinal tract. Mammals with lipid (fat) malabsorption diseases such as Cystic fibrosis, Crohn's disease, Short bowel syndrome and the like, present special problems for the digestion, absorption and lymphatic transport of dietary fat and lipophilic compounds, such as drugs, hormones, nutrients and vitamins since the underlying disease limits the absorption and transport of the lipophilic compound from the gut. Absorption of lipophilic compounds is thus impaired in diseases that cause fat malabsorption.
The development of special dosage forms and the use of various absorption promoters for lipophilic compounds have been extensively studied. For example, Hansen et al. in WO92/109237 disclose the use of specific triglycerides in an enteral preparation for the treatment of lipid malabsorption. This reference specifically discloses the use of a purified lipid having a medium chain acyl moiety at the sn-1 and sn-3 positions and a long chain acyl moiety at the sn-2 position.
U.S. Pat. No. 4,753,963 to Jandacek et al. discloses a nutritional fat suitable for enteral and parenteral products. This patent claims a triglyceride having an N-octanoyl acyl radical or moiety at the sn-1 and sn-3 positions. The sn-2 acyl radical comprises saturated acyl groups selected from the group consisting of N-heptanoyl, N-octanoyl, N-nonanoyl, N-decanoyl, N-undecanoyl, lauroyl, myristoyl, palmitoyl, and stearoyl. This reference also discloses the use of these fats in enteral products comprising carbohydrates, a source of amino acids and optionally, components such as vitamins and minerals.
DeMichele et al. in U.S. Pat. No. 5,661,180 discloses a structured lipid containing a gamma-linolenic acid or a dihomogamma-linolenic acid moiety together with an n-3 fatty acid residue and a medium chain fatty acid moiety. The DeMichele structured lipid is disclosed as being well adapted to the treatment of disease or stress states. This reference also teaches the use of the specific structured lipid to modulate metabolic response associated with trauma and inflammatory disease states.
U.S. Pat. No. 4,871,768 to Bistrian et al. discloses a structured lipid comprising n-3 fatty acid moieties and medium chain fatty acid moieties. More specifically, this patent discloses a synthetic triglyceride comprising a glycerol backbone having three fatty acids esterfied thereto wherein the fatty acids are selected from a first group consisting of n-3 fatty acids and a second group consisting of caprylic acid, capric acid and mixtures thereof. This patent discloses the structured lipids as a dietary supplement for enhancing resistance to infection while providing good nutrition and an excellent source of energy. This reference, like those above, is directed to the use of structured lipids for nutritional value.
International Publication. No. WO95/31110 to Lien et al. discloses a co-randomized fat composition for use in nutritional products for pre-term and low birth weight infants. This reference discloses the co-randomization of oils such as palmitic acid oil and an oleic acid oil to yield a mixture of triglycerides having a substantially different chemical profile than that of the starting materials. This reference discloses the use of these specific structured lipids in enteral or parenteral products for infants to approach the fatty acid profile of human milk.
European Patent Application No. 0 347 843 to Tsushima et al. discloses the improved absorption of vitamin E by the digestive system through the use of lecithin and a free unsaturated fatty acid. This reference discloses the free unsaturated fatty acid as preferably being oleic acid or linoleic acid. This reference teaches improved absorption of vitamin E through the combined administration of vitamin E with lecithin (phosphatidylcholine derived from egg yolk or soy beans) in combination with a free unsaturated fatty acid such as linoleic acid or oleic acid.
Kimura et al. in Chem Pharm. Bull., 37(2) 439-441 (1989) entitled, "Enhancement of Oral Bioavailability of d-.alpha.-Tocopherol Acetate by Lecithin-Dispersed Aqueous Preparation Containing Medium-Chain Triglycerides in Rats" reports the use of vitamin E/lecithin-dispersed aqueous preparations which increase the lymphatic absorption of vitamin E. This reference also investigated the use of polysorbate 80-solubilized aqueous emulsions of vitamin E and its absorption through the intestinal mucosa. These investigators found that the administration of MCT significantly enhanced the absorption of lecithin-dispersed aqueous preparations of vitamin E by the gastrointestinal tract. It is well established that the absorption of MCT occurs mainly via the portal circulation and not via the lymphatic route. In contrast, vitamin E is transported predominantly via the lymphatic system. It appears from this reference that the mechanism of absorption of vitamin E does not resemble the intestinal transport of MCT.
Two publications by Fukui et al., J. Pharmacobio-Dyn., 12, 80-86 (1989) and J. Pharmacobio-Dyn., 12, 754-761 (1989) report the enhancing effect of MCT on intestinal absorption of vitamin E as does the Kimura et al. reference above. These two references also support the conclusion that MCT absorption and vitamin E absorption use unrelated pathways.
Chen et al. report in "Absorption of Tocopherol in Intestinal Lymph Fistula Rat: Effects of Triolein and Phosphatidylcholine" Gastroenterology 108:A720, (1995), that the absorption of vitamin E is influenced by the presence of triolein (triglyceride) and phosphatidylcholine (lecithin). The use of lecithin promotes the water miscibility of the vitamin E. When the same amount of fatty acid was infused in the form of triolein or phosphatidylcholine with vitamin E, the amount of lipid transported to the lymph was similar. In contrast, the transport of vitamin E into lymph was significantly reduced in the animals infused with phosphatidylcholine as compared to those infused with the triglyceride. It thus appears from this work that it is not possible to predict the level of absorption of vitamin E based on the efficiency of triglyceride absorption.
The inclusion of polyunsaturated fatty acids in bile salt micelles is reported to depress .alpha.-tocopherol absorption by the rat small intestine. See Muralidhara et al., "Intestinal Absorption of .alpha.-Tocopherol in the Unanesthetized Rat. The Influence of Luminal Constituents on the Absorptive Process." J. Lab. Clin. Med., 90:85-91, (1977). It is known that polyunsaturated fatty acids are well absorbed by the gastrointestinal tract. However, Muralidhara et al. demonstrates that the absorption of vitamin E is suppressed by the presence of polyunsaturated fatty acids. The experiments indicate that micellar expansion with polyunsaturated fatty acids interferes with the absorption of tocopherol and may result in deficiency of the vitamin. This reference also supports the belief that better triglyceride absorption is not always associated with enhanced absorption of fat soluble vitamins.
MacMahon et al. have demonstrated in rats with bile diversion that a polar lipid such as oleic acid, is well absorbed into the lymphatic system from an emulsion (from bile salt micelles) while the non-polar .alpha.-tocopherol was poorly absorbed from the emulsion. See MacMahon et al. "Comparison of the Absorption of a Polar Lipid, Oleic Acid, and a Non-Polar Lipid, .alpha.-Tocopherol from Mixed Micellar Solutions and Emulsions", European Journal of Clinical Investigation 1:160-166, 1970. This publication also supports the position that good triglyceride absorption, from an emulsion, is not always associated with good vitamin absorption.